10 Propargyl 5

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G M F Bisset - One of the best experts on this subject based on the ideXlab platform.

  • quinazoline antifolates inhibiting thymidylate synthase synthesis of γ linked peptide and amide analogues of 2 desamino 2 methyl n10 Propargyl 5 8 dideazafolic acid ici 198583 10 Propargyl 5 8 dideazafolic acid ici 198583
    Advances in Experimental Medicine and Biology, 1993
    Co-Authors: Vassilios Bavetsias, A L Jackman, T J Thornton, Krzysztof Pawelczak, Thomas F Boyle, G M F Bisset
    Abstract:

    Thymidylate Synthase (TS) inhibitors such as ICI D16941 and to lesser extent ICI 1985832 rely on their poly-γ-glutamate metabolites for their antitumour activity. The polyglutamate metabolites are more potent inhibitors of TS than the parent monoglutamate forms and in addition, their polyionic nature leads to prolonged retention within the cells. However, drugs dependent on polyglutamation may have some disadvantages such as a) lack of activity in tumours expressing low levels of, or an altered expression of, folylpolyglutamate synthetase (FPGS) or b) prolonged normal tissue toxicities caused by polyglutamate retention. For these reasons, we were interested in designing and synthesising tight-binding TS inhibitors which would not be dependent on polyglutamation for antitumour activity. Addition of one glutamate residue on the γ-carboxyl of 2-desamino-2-methyl-N10-Propargyl-5,8-dideazafolic acid (ICI 198583), i.e. dipeptide (1), resulted in stronger binding to TS by approximately 30-fold2. This finding was the starting point in our search for a tight TS inhibitor that could not be a substrate for FPGS. We report here the synthesis of 22 dipeptide and 6 γ-amide analogues of ICI 198583-γ-L-Glu.

Vassilios Bavetsias - One of the best experts on this subject based on the ideXlab platform.

  • quinazoline antifolates inhibiting thymidylate synthase synthesis of γ linked peptide and amide analogues of 2 desamino 2 methyl n10 Propargyl 5 8 dideazafolic acid ici 198583 10 Propargyl 5 8 dideazafolic acid ici 198583
    Advances in Experimental Medicine and Biology, 1993
    Co-Authors: Vassilios Bavetsias, A L Jackman, T J Thornton, Krzysztof Pawelczak, Thomas F Boyle, G M F Bisset
    Abstract:

    Thymidylate Synthase (TS) inhibitors such as ICI D16941 and to lesser extent ICI 1985832 rely on their poly-γ-glutamate metabolites for their antitumour activity. The polyglutamate metabolites are more potent inhibitors of TS than the parent monoglutamate forms and in addition, their polyionic nature leads to prolonged retention within the cells. However, drugs dependent on polyglutamation may have some disadvantages such as a) lack of activity in tumours expressing low levels of, or an altered expression of, folylpolyglutamate synthetase (FPGS) or b) prolonged normal tissue toxicities caused by polyglutamate retention. For these reasons, we were interested in designing and synthesising tight-binding TS inhibitors which would not be dependent on polyglutamation for antitumour activity. Addition of one glutamate residue on the γ-carboxyl of 2-desamino-2-methyl-N10-Propargyl-5,8-dideazafolic acid (ICI 198583), i.e. dipeptide (1), resulted in stronger binding to TS by approximately 30-fold2. This finding was the starting point in our search for a tight TS inhibitor that could not be a substrate for FPGS. We report here the synthesis of 22 dipeptide and 6 γ-amide analogues of ICI 198583-γ-L-Glu.

James R Piper - One of the best experts on this subject based on the ideXlab platform.

  • analogues of methotrexate in rheumatoid arthritis 2 effects of 5 deazaaminopterin 5 10 dideazaaminopterin and analogues on type ii collagen induced arthritis in mice
    Journal of Medicinal Chemistry, 1997
    Co-Authors: James R Piper, J I Degraw, W T Colwell, Cheryl A Johnson, R L Smith, W R Waud, F M Sirotnak
    Abstract:

    Twenty-six compounds derived from the 5-deaza- and 5,10-dideazaaminopterin series of aminopterin analogues were evaluated for antiarthritic activity in the mouse type II collagen model. New compounds in the 5-deaza series were prepared by alkylation of an appropriate N-substituted (4-aminobenzoyl)-L-glutamic acid dialkyl ester or N-(5-amino-2-thenoyl)-L-glutamate diester with a 2,4-diamino-5-alkyl-6-(bromomethyl)-5-deazapteridine. The resultant 5-deazaaminopterin diesters were saponified to provide the target 5-deaza analogues. 5,10-Dideazaaminopterins were synthesized by similar alkylation of the carbanions of appropriate 4-carboxyphenylacetic, (5-carboxy-2-thienyl)acetic, or (5-carboxy-2-pyridyl)acetic acid dimethyl esters. The diesters of the 2,4-diamino-4-deoxy-10-carboxy-5,10-dideazapteroic acid types so obtained were saponified and then readily decarboxylated by heating in Me2SO solution to provide the 2,4-diamino-5,10-dideazapteroic acid-type intermediates. Peptide coupling with diethyl L-glutamate followed by ester hydrolysis at room temperature afforded the new 5,10-dideazaaminopterin analogues. 5-Deazaaminopterins bearing an alkyl substituent at the 5-position were generally quite effective as antiinflammatory agents. Thus 5-propyl-5-deazaaminopterin, 5-methyl-10-Propargyl-5-deazaaminopterin, 5-methyl-10-allyl-5-deazaaminopterin, 5-ethyl-5-deazamethotrexate, and 2,5-disubstituted thiophene analogue of 5-methyl-5-deazaaminopterin showed potencies greater than methotrexate by intraperitoneal or oral administration and were active over a considerably broader dose range. Useful activity in the 5,10-dideaza series was only observed for 5,10-dideazaaminopterin and its 10-methyl analogue. Alkyl substitution at C-5 or C-10 was generally detrimental to antiinflammatory activity in this series.

  • synthesis and antifolate evaluation of the 10 Propargyl derivatives of 5 deazafolic acid 5 deazaaminopterin and 5 methyl 5 deazaaminopterin
    Journal of Medicinal Chemistry, 1992
    Co-Authors: James R Piper, Neeta D Malik, M S Rhee, J Galivan, Francis M Sirotnak
    Abstract:

    5-Deaza-10-Propargylfolic acid (4), an analogue of the thymidylate synthase (TS) inhibitor 10-Propargyl-5,8-dideazafolic acid (PDDF, 1), was prepared via alkylation of diethyl N-[4-(Propargylamino)benzoyl]-L-glutamate (7) by 2-amino-6-(bromomethyl)-4(3H)-pyrido[2,3-d]pyrimidinone (15). Bromomethyl intermediate 15 was prepared from the corresponding hydroxymethyl precursor 14 by treatment with 48% HBr. Hydroxymethyl compound 14 was obtained by deamination of reported 2,4-diaminopyrido[2,3-d]pyrimidine-6-methanol (12a) in refluxing 1 N NaOH. Both 12a and its 5-methyl-substituted analogue 12b were converted to versatile 6-bromomethyl intermediates 13a and 13b from which important antifolates may be readily derived. Alkylation of 7 by 13a,b led to 10-Propargyl-5-deazaaminopterin (5) and 5-methyl-10-Propargyl-5-deazaaminopterin (6). As an inhibitor of TS from H35F/F cells, 4 gave an IC50 value showing it to be approximately 6-fold less inhibitory than PDDF (90 nM for 4 vs 14 nM for PDDF). In in vitro studies, IC50 (microM) values obtained for 4 vs L1210 and S180 of 1.50 and 2.35, respectively, were similar to those obtained for PDDF (2.61 and 1.97). Against HL60 cells, 4 was about 7-fold more cytotoxic than PDDF (IC50 values 0.72 and 5.29 microM). Inclusion of thymidine did not establish TS as the site of cytotoxic action for either 4 or PDDF in the cell lines used. In in vivo tests against L1210 in mice, 4 failed to show therapeutic effect. The 2,4-diamino compounds 5 and 6 were as potent inhibitors of DHFR from L1210 cells as MTX and 7- and 35-fold, respectively, more inhibitory than MTX toward L1210 cell growth. In mediated influx into L1210 cells, 5 and 6 were transported 2.7- and 8.5-fold, respectively, more readily than MTX. Against the EO771 mammary adenocarcinoma in mice, 6 produced greater antitumor effect than MTX. A dose of 36 mg/kg per day for 5 days caused no toxic deaths while the average tumor volume among 10 mice was reduced to 8-9% of that of the control, and 20% of the test animals were rendered tumor free.

A L Jackman - One of the best experts on this subject based on the ideXlab platform.

  • quinazoline antifolates inhibiting thymidylate synthase synthesis of γ linked peptide and amide analogues of 2 desamino 2 methyl n10 Propargyl 5 8 dideazafolic acid ici 198583 10 Propargyl 5 8 dideazafolic acid ici 198583
    Advances in Experimental Medicine and Biology, 1993
    Co-Authors: Vassilios Bavetsias, A L Jackman, T J Thornton, Krzysztof Pawelczak, Thomas F Boyle, G M F Bisset
    Abstract:

    Thymidylate Synthase (TS) inhibitors such as ICI D16941 and to lesser extent ICI 1985832 rely on their poly-γ-glutamate metabolites for their antitumour activity. The polyglutamate metabolites are more potent inhibitors of TS than the parent monoglutamate forms and in addition, their polyionic nature leads to prolonged retention within the cells. However, drugs dependent on polyglutamation may have some disadvantages such as a) lack of activity in tumours expressing low levels of, or an altered expression of, folylpolyglutamate synthetase (FPGS) or b) prolonged normal tissue toxicities caused by polyglutamate retention. For these reasons, we were interested in designing and synthesising tight-binding TS inhibitors which would not be dependent on polyglutamation for antitumour activity. Addition of one glutamate residue on the γ-carboxyl of 2-desamino-2-methyl-N10-Propargyl-5,8-dideazafolic acid (ICI 198583), i.e. dipeptide (1), resulted in stronger binding to TS by approximately 30-fold2. This finding was the starting point in our search for a tight TS inhibitor that could not be a substrate for FPGS. We report here the synthesis of 22 dipeptide and 6 γ-amide analogues of ICI 198583-γ-L-Glu.

Thomas F Boyle - One of the best experts on this subject based on the ideXlab platform.

  • quinazoline antifolates inhibiting thymidylate synthase synthesis of γ linked peptide and amide analogues of 2 desamino 2 methyl n10 Propargyl 5 8 dideazafolic acid ici 198583 10 Propargyl 5 8 dideazafolic acid ici 198583
    Advances in Experimental Medicine and Biology, 1993
    Co-Authors: Vassilios Bavetsias, A L Jackman, T J Thornton, Krzysztof Pawelczak, Thomas F Boyle, G M F Bisset
    Abstract:

    Thymidylate Synthase (TS) inhibitors such as ICI D16941 and to lesser extent ICI 1985832 rely on their poly-γ-glutamate metabolites for their antitumour activity. The polyglutamate metabolites are more potent inhibitors of TS than the parent monoglutamate forms and in addition, their polyionic nature leads to prolonged retention within the cells. However, drugs dependent on polyglutamation may have some disadvantages such as a) lack of activity in tumours expressing low levels of, or an altered expression of, folylpolyglutamate synthetase (FPGS) or b) prolonged normal tissue toxicities caused by polyglutamate retention. For these reasons, we were interested in designing and synthesising tight-binding TS inhibitors which would not be dependent on polyglutamation for antitumour activity. Addition of one glutamate residue on the γ-carboxyl of 2-desamino-2-methyl-N10-Propargyl-5,8-dideazafolic acid (ICI 198583), i.e. dipeptide (1), resulted in stronger binding to TS by approximately 30-fold2. This finding was the starting point in our search for a tight TS inhibitor that could not be a substrate for FPGS. We report here the synthesis of 22 dipeptide and 6 γ-amide analogues of ICI 198583-γ-L-Glu.